The current proposal is for continuation of our studies with two model systems for HTLV-1 infection, an infectious molecular clone and Tax transgenic mice. These studies focus on Tax, which appears to e the primary oncogenic determinant of HTLV-1. The aims are: 1) To assess the mechanism of action of Tax in lymphocyte immortalization by the infectious molecular clone-We will analyze Tax mutation defective in transcriptional transactivation through CREB or NF kappaB to determine the requirement for immortalization of human lymphocytes in culture and HTLV-1 replication in rabbits. We will determine if effects of Tax on immortalization can be separated from effects on virus replication. 2) To assess the mechanism of action of Tax induction of lymphoproliferative disease in transgenic mice-We will assess the spectrum of lymphoid malignancies in Tax transgenic mice in TCR transgenic mice inoculated with ovalbumin, recognized by the TCR. We will assess the role of inactivation will be assessed in Tax transgenic mice by sequence analysis of mutated p53 alleles and by analyzing the lymphoproliferative disease in Tax transgenic, p53 -/- mice. These studies utilize 2 unique model systems to define the leukemogenic pathway mediated by HTLV-1.